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Nassef M.,Kyushu University | Matsumoto S.,Kyushu University | Seki M.,Chemicals Evaluation and Research Institute CERI | Khalil F.,Kyushu University | And 4 more authors.
Chemosphere | Year: 2010

The toxicity of three pharmaceutical and personal care products (PPCPs) - carbamazepine (CBMZ), diclofenac (DCF), and triclosan (TCS) - was examined by measuring their effects on feeding behavior and swimming speed of adult Japanese medaka fish (Oryzias latipes). Medaka were exposed to 6.15mgL -1 CBMZ, 1.0mgL -1 DCF, 0.17mgL -1 TCS, or no PPCP (control) for 9d. Fish behaviors were monitored during days 5-9 of the exposure period. Feeding behavior (time to eat midge larvae, TE) and swimming speed (SS) of individual exposed and control fish were tracked in two dimensions, using an automated system with a digital charge-coupled device camera. As a result, feeding behavior was affected by exposure to CBMZ and DCF, while SS was altered by exposure to CBMZ and TCS. Thus, TCS, DCF and CBMZ appear to affect fish behaviors through different mechanisms. Overall, the results suggest that behavioral changes may provide a sensitive indicator for assessing the toxicity of PPCPs to aquatic organisms. © 2010 Elsevier Ltd. Source

Yokota H.,Kobe College | Eguchi S.,Kobe College | Nakai M.,Chemicals Evaluation and Research Institute CERI
Aquatic Toxicology | Year: 2011

A global effort has been made to establish screening and testing methods that can identify the effects of endocrine-disrupting chemicals (EDCs) on invertebrates. The purpose of our study was to develop an in vitro receptor binding assay for ecdysone receptor (EcR) in mysid shrimp (Americamysis bahia). We cloned mysid shrimp EcR cDNA (2888 nucleotides) and ultraspiracle (USP) cDNA (2116 nucleotides), and determined that they encode predicted proteins of length 570 and 410 amino acids, respectively. The deduced amino acid sequences of these proteins shared 36-71% homology for EcR and 44-65% for USP with those of other arthropods. Phylogenetic analysis revealed that mysid shrimp EcR was classified into an independent cluster together with the EcRs of another mysid species, Neomysis integer and the cluster diverged early from those of the other taxonomic orders of crustaceans. We then expressed the ligand-binding domains (DEF regions) of mysid shrimp EcR (abEcRdef) and USP (abUSPdef) as glutathione S-transferase (GST)-fusion peptides in Escherichia coli. After purifying the fusion peptides by affinity chromatography and removing the GST labels, we subjected the peptides to a ligand-receptor binding assay. [ 3H]-ponasterone A did not bind to abEcRdef or abUSPdef peptides alone but bound strongly to the abEcRdef/abUSPdef mixture with dissociation constant (K d)=2.14nM. Competitive binding assays showed that the IC 50 values for ponasterone A, muristerone A, 20-hydroxyecdysone, and α-ecdysone were 1.2, 1.9, 35, and 1200nM, respectively. In contrast, the IC 50 values for two dibenzoylhydrazine ligands (tebufenozide and chromafenozide) were >1.0×10 5nM. The intra- and inter-assay coefficient of variation values for the IC 50 values of 20-hydroxyecdysone were 14.7% (n=5) and 16.1% (n=8), respectively. Our results indicate that the binding assay with a mixture of abEcRdef and abUSPdef can be used to screen compounds with a broad range of binding affinities for crustacean EcRs. © 2011 Elsevier B.V. Source

Kohda M.,Saitama University | Tokuzawa Y.,Saitama University | Kishita Y.,Saitama University | Nyuzuki H.,Saitama University | And 32 more authors.
PLoS Genetics | Year: 2016

Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder. © 2016 Kohda et al. Source

Shinohara N.,Japan National Institute of Advanced Industrial Science and Technology | Oshima Y.,Chemicals Evaluation and Research Institute CERI | Kobayashi T.,Chemicals Evaluation and Research Institute CERI | Imatanaka N.,Chemicals Evaluation and Research Institute CERI | And 6 more authors.
Toxicology | Year: 2014

AEROSIL® P25 titanium dioxide (TiO2) nanoparticles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats at doses of 0 (control), 0.375, 0.75, 1.5, 3.0, and 6.0mg/kg. The rats were sacrificed under anesthesia at 1 day, 3 days, 7 days, 4 weeks, 13 weeks, and 26 weeks after administration. Ti levels in various pulmonary and extrapulmonary organs were determined using sensitive inductively coupled plasma sector field mass spectrometry. One day after administration, the lungs contained 62-83% of TiO2 administered dose. Twenty-six weeks after administration, the lungs retained 6.6-8.9% of the TiO2 administered at the 0.375, 0.75, and 1.5mg/kg doses, and 13% and 31% of the TiO2 administered at the 3.0 and 6.0mg/kg doses, respectively. The pulmonary clearance rate constants from compartment 1, k1, were estimated using a 2-compartment model and were found to be higher for the 0.375 and 0.75mg/kg doses of TiO2 (0.030/day for both) than for TiO2 doses of 1.5-6.0mg/kg (0.014-0.022/day). The translocation rate constants from compartment 1 to 2, k12, were estimated to be 0.015 and 0.018/day for the 0.375 and 0.75mg/kg doses, and 0.0025-0.0092/day for doses of 1.5-6.0mg/kg. The pulmonary clearance rate constants from compartment 2, k2, were estimated to be 0.0086 and 0.0093/day for doses of 0.375 and 0.75mg/kg, and 0-0.00082/day for 1.5-6.0mg/kg doses. Translocation of TiO2 from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner, accounting for 0.10-3.4% of the administered dose at 26 weeks. The measured thoracic lymph node burdens were a much better fit to the thoracic lymph node burdens estimated assuming translocation from compartment 1 to the thoracic lymph nodes, rather than those estimated assuming translocation from compartment 2 to the thoracic lymph nodes. The translocation rate constants from the lungs to the thoracic lymph nodes, kLung→Lym, were 0.000037-0.00081/day, and these also increased with increasing doses of TiO2. Although a small amount of TiO2 had translocated to the liver by 3 days after the administration (0.0023-0.012% of the highest dose administered, 6.0mg/kg), translocation to the other extrapulmonary organs was not detected. © 2014 Elsevier Ireland Ltd. Source

Ishii S.,Chemicals Evaluation and Research Institute CERI | Ishii K.,Chemicals Evaluation and Research Institute CERI | Nakadate M.,Chemicals Evaluation and Research Institute CERI | Yamasaki K.,Chemicals Evaluation and Research Institute CERI
Food and Chemical Toxicology | Year: 2013

The purpose of this study was to investigate the correlations in skin and eye irritations between rabbits and humans using published international databases. We selected 60 and 56 compounds for skin and eye irritation, respectively. When the reactions were divided into irritation-negative or irritation-positive, including corrosion, similar reactions between rabbits and humans were detected for 53 compounds in skin irritation and 54 compounds in eye irritation, showing rates of agreement in skin and eye as 88% and 96%, respectively. These findings revealed that correlation in skin and eye irritations between rabbits and humans were high. However, corrosion was observed in rabbit skin treated with 14 compounds, 4 of which showed similar changes in humans, and in rabbit eyes treated with 9 compounds, 1 of which revealed similar changes in humans. These findings indicated that the incidence of corrosion was higher in rabbits than in humans. Our results showed that the data on rabbit irritations in the skin and eye were useful for identifying risk of irritation in human. © 2013 Elsevier Ltd. Source

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